Penanganan DM

tipe 2

Dr Budi Enoch SpPD

16 Maret 2013
 Tantangan diabetes
By the year 2030,
350 million people
will have
type 2 diabetes
(21,3 million from
Indonesia- top 4)
• 2020 : Penduduk Indonesia diatas usia 20 tahun
178.000.000 orang dimana 7.000.000 orang (4%)
adalah penderita DM tipe 2
• Berdasarkan hasil Riset Kesehatan Dasar (Riskesdas)
2007, angka prevalensi diabetes mellitus tertinggi
terdapat di provinsi Kalimantan Barat dan Maluku
Utara (masing-masing 11,1 persen), diikuti Riau
(10,4 persen) dan NAD (8,5 persen).
• NDDM : resiko CHD 2 – 4 kali lebih tinggi dibanding
non DM2
• Biaya perawatan DM, 10% dari total ongkos
perawatan kesehatan1
• Penyakit CV mengkonsumsi proporsi biaya terbesar
dari ‘direct costs2’
1. International Diabetes Federation, Diabetes Atlas, 4th Edition;
2. Diabetes - The Policy Puzzle. FEND 2003
 Biaya langsung dan tidak langsung untuk
diabetes
• 1 dari setiap 7 dollar biaya perawatan kesehatan
digunakan untuk orang dengan diabetes
• Biaya perawatan kesehatan untuk orang dengan
diabetes setiap tahun berlipat 3,6 kali lebih besar
daripada biaya perawatan kesehatan pada orang
tanpa diabetes
• Biaya langsung untuk kasus positif: 85 milyar dollar
• Perkiraan biaya secara keseluruhan: 92 – 100 milyar
dollar
 Healthcare expenditures attributable to
diabetes

% of Total

Routine follow-up 32.5

Acute Metabolic Conditions 6.2

Chronic complications 61

ADA Diabetes Caro 21: 296, 1968

Pathophysiology of type 2 diabetes
Where are we in 2013
 Natural History of Type II DM
obesity Impaired diabetes Uncontrolled
glucosa hyperglycae
tolerance mia

pp

n
120
mgr%

-20 -10 0 +10 +20 +30

Years of diabetes
 Natural History of Type II DM
obesity Impaired diabetes Uncontrolled
glucosa hyperglycae
tolerance mia
Relative β cells function

Insulin resistance

100%

Decline β cell Insulin level

function

-20 -10 0 +10 +20 +30

Years of diabetes
 Komplikasi diabetes
Microvascular
• Retinopathy
• Neuropathy
• Nephropathy
Macrovascular
• Cerebrovascular disease
• Peripheral vascular disease
• Coronary heart disease
 Diagnosis

Pilar Pengobatan
I II III IV

edukasi Aktifitas nutrisi obat

fisik

Edukator Dokter
 Major Classes of Medications

1. Drugs that sensitize the Thiazolidinediones

body to insulin and/or Biguanides
control hepatic glucose *Inlacin
production

2. Drugs that stimulate the Sulfonylureas

pancreas to make more Meglitinides
insulin

3. Drugs that slow the Alpha-

glucosidase
absorption of starches inhibitors
 Pros and cons of diabetes therapies1
GLP-1
receptor DPP-4
Metformin SU Pioglitazone Insulin
inhibitors
agonist

Efficacy ++ ++ ++ +++ ++ ++

Cardiovascular
Outcome No No
Yes Yes Yes Yes
(in progress) (in progress)
Studies
Hypoglycaemia
as consequence
of individual Low Higher* Low Higher* Low Low
drug

Weight gain No Yes Yes Yes Weight loss No

Fluid retention, Gastrointestinal

Gastro- Hypoglycaemia, side effects,
Hypoglycaemia, Increased risk of Long term safety
Disadvantages intestinal side Weight gain osteoporosis and Weight gain Long term safety not established
effects
fractures not established

*compared to non-insulin secretagouges

1. Nathan DM, et al. Diabetologia. 2009;52:17-30.

Class I • Prevention of microvascular disease
recommendation “evidence or general agreement that a
given Tx is useful or effective”

Class IIb • Prevention of macrovascular disease

recommendation “usefulness or efficacy is less well
established by evidence or opinion”
 Keuntungan intervensi yang berbeda
per 200 pasien diabetes yang dirawat selama 5
tahun
5
Per 4 mmHg Per 1 mmol/L Per 0.9%
lower SBP lower LDL-C lower HbA1c
0 2
1
CV events

9% *
-5 -2,9

-8,2
-10

-15 -12,5

-20

Ray KK et al. Lancet 2009;373:1765–72

 Tantangan pelaksanaan kontrol glukosa darah

Hypoglycaemia /
Weight gain

HbA1c
 Mengapa hypoglycaemia penting
• Hypoglycaemia mempunyai kaitan dengan bertambahnya
mortalitas 1
• Sampai 38% pasien dengan diabetes type 2 melaporkan
adanya symptomatic hypoglycaemia2
• Hypoglycaemia mengakibatkan menurunnya kualitas
hidup, kepuasan perawatan dan ketaatan terhadap
pengobatan 2
• Hypoglycaemia merupakan penghalang (barrier) bagi titrasi
dosis insulin optimal dan pencapaian kontrol glycaemic
• Hanya 15% pasien dengan diabetes type 2 yang mengalami
hypoglycaemia, melaporkan kejadian tersebut pada dokter
mereka 3
1. Bonds DE et al 2010 Jan 8;340:b4909. doi: 10.1136/bmj.b4909
2. Diabetes Obesity and metabolism 2008 Jun;10 Suppl 1:25-32
3. McAulay V et al. Diabet Med. 2001; 18: 690–705
 Kaplan-Meier estimates of the proportion of
participants with at least one episode of
hypoglycaemia requiring medical assistance in
the ACCORD study

Miller, M. E et al. BMJ 2010;340:b5444

 Siapa saja yang mempunyai resiko?

• Tingkat hypoglycaemia yang lebih tinggi

berkaitan dengan dengan terapi intensif (3.14 vs.
1.03 dan 5.05 vs. 1.51 kasus / 100 orang tahun)
• Resiko bertambah di antara –
Manula
African Americans
Yang berpendidikan rendah
Menderita diabetes dalam jangka waktu lama
Insulin
Peripheral neuropathy
Disfungsi ginjal
Miller ME et al BMJ 2010
 HbA1c dan hypoglycaemia
• Penurunan awal HbA1c secara cepat, tidak berhubungan
dengan meningkatnya resiko
• Untuk setiap 1% ↓ HbA1c selama 4 bulan pertama - ↓
resiko sebanyak 28% pada kelompok perawatan standard
dan 14% pada kelompok perawatan intensive
• Peningkatan resiko terjadi pada mereka yang mempunyai
baseline HbA1c yang lebih tinggi (hanya pada kelompok
dengan perawatan standard!)
• Resiko Hypoglycaemia meningkat pada tiap 1% ↑ dalam
rata-rata HbA1c yang diperbaharui, pada kedua kelompok
(standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06;
intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21)
Miller ME et al BMJ 2010
 Hypoglycaemia – clinical consequences
• Hypoglycaemia has proarrhythmic effects1
Q-T interval prolongation
Ca++ Channel overload
Suppression of K+ channel activation during repolarisation
Autonomic nervous system over activation
• Hypoglycaemia associated with cognitive
dysfunction and delayed recovery in the elderly2
• Hypoglycaemia associated with increased anxiety3
• Hypoglycaemia linked to pro-thrombotic and pro-
inflammatory effects4
1. Nordin Diabetologia (2010) 53:1552–1561
2. Zammitt Diabetes. 2008;57(3):732-6
3. Labad Diabetologia. 2010;53(3):467-71.
4. Wright Diabetes Care. 2010;33(7):1591-7
 How low should it go?
Adjusted hazard ratios for all-cause mortality by HbA 1c deciles in people given
oral combination and insulin-based therapies

Metformin plus sulphonylureas Insulin-based regimens

Currie et al. Lancet 2010;375(9713):481–9

 Which HbA1c to target?

HbA1c goal Individual targeted HbA1c

•Short duration of diabetes

6,5 – 7% •Long life expectancy
•No significant CVD
•Major focus on primary prevention of complications

Justification •Reduced risk for microvascular complication

•Reduced risk for macrovascular complication in the long run

•History of hypoglycemia
7,0 – 8% •Limited life expectancy
•Advanced microvascular or macrovascular complications
•Extensive co-morbid conditions

Diabetes Care 2010;33(Suppl 1):S11-S61

Composite end points that matter

HbA1c <7.0%
+
No weight gain
+
No hypoglycaemia
 Kesimpulan
 Kontrol glycaemic ketat dini berkaitan dengan penurunan
signifikan:
− Angka kematian keseluruhan
− Kematian karena CVD
− Kejadian vascular
 Dalam waktu lama, pada pasien dengan resiko tinggi,
kontrol glycaemic yang “terlalu ketat” atau “terlalu cepat
melakukan pengetatan” dapat menambah kesempatan
terjadinya arrhythmias/CVD dan kematian, kemungkinan
disebabkan oleh resiko hypoglycaemia
 Menentukan target dan terapi berdasarkan individu
merupakan hal yang vital
 Obat-obat baru (mis. terapi incretin-based) mempunyai
potensi memperbaiki kontrol glycaemic dengan resiko
rendah terjadinya hypoglycaemia dan penambahan berat
badan
Improvement of Insulin Resistance with
Inlacin (Bioactive Fraction DLBS 3233)
 Normal Insulin Signalling
STIMULATION OF
GLUCOSE
INSULIN – RECEPTOR
TRANSPORT CELL
GLUT-4 BINDING
MEMBRANE
EXERCISE

ATP
5’-AMP-
ACTIVATED PROTEIN
KINASE B
KINASE (PKB) / Akt TYROSINE
PHOSPHORYLATION
TRANSLOCATIO PHOSPHOINOSITIDE-
Exercise- N TO CELL DEPENDENT
p110 p85 IRS
Responsive MEMBRANE KINASES
GLUT-4 – PHOSPHOINOSITIDE-
Containing ATYPICAL SH2
Vesicle PROTEIN 3 KINASE (PI-3K)
KINASE C Domains

Insulin-
Responsive
GLUT-4 –
Containing
Vesicle
 Effects of Tyrosine and Serine
Phosphorylations
Alpha Sub Unit Tyrosine Site of Insulin Binding
Kinase Receptor

α α Cell Membrane

Insulin Sensitivity β β
Tyr / Ser Tyr / Ser Cellular Response
Tyrosine
Tyr / Ser Tyr / Ser IRS
Phosporylation
Tyr / Ser Tyr / Ser

Serine P Tyrosine: Increase

Insulin Sensitivity
Beta Sub Unit Tyrosine
Insulin Resistance Kinase Receptor P Serine: Causes Insulin
Resistance
 Effects of Inlacin in Inhibiting Serine
Phosphorylation
Site of Insulin Binding
I I

α α Cell Membrane
X β β
FFA Cellular Response
ATP ADP P Tyr P
P Tyr P
TNFα
_ P Tyr P Cellular Response

Inlacin:
Inhibit Serine Phosphorylation
 Reducing the action of TNF Alpha
 Reducing FFA
 Increasing Insulin Sensitivity
PPARg activation decreases insulin resistance
and chronic PKC translocation
 Inlacin Increases Insulin Sensitivity by
Tyrosine Phosphorylation
Site of Insulin Binding

α α Cell Membrane

β β
P Tyr P Insulin Sensitivity
Phosporylation P Tyr P
ATP ADP
P Tyr P Insulin Sensitivity

P Tyrosine: Increase Insulin Sensitivity

How Increased Lipolysis
leads to Hyperglycemia
 Inlacin Decreases Lipolysis
INSULIN – RECEPTOR BINDING

IRS-PTyrosine
PKC  and PKC 
TRANSLOCATION

CELLULAR
 FFA P Tyr P
RESPONSE
P Tyr P
ATP ADP P Tyr P
CELLULAR
 TNF  RESPONSE

INLACIN®

 INSULIN  INSULIN
SENSITIVITY TYROSINE PHOSPHORYLATION SENSITIVITY
Inlacin (DLBS3233) lowers Plasma Lipid
INLACIN (DLBS3233)
In Vivo Study
DLBS 3233 Monotherapy Decreases Random,
Fasting and Postprandial Glucose
Comparison of Insulin level and Fasting
Glucose level
Effects of DLBS32 +/- Metformin on
Fasting Glucose Levels

160

150

140
Insulin Resistant
Fasting BG 130
Metformin
(mg/dl)
120 DLBS3233
Metformin + DLBS3233
110

100
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
Effects of DLBS32 +/- Metformin on Fasting Total
Cholesterol and Trigliceride Levels
220

200

Total 180
Cholesterol Insulin Resistant
Metformin
(mg/dl) 160 DLBS3233
Metformin + DLBS3233
140

120
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment

160

140

Triglyceride 120

(mg/dl) 100
Insulin Resistant
80
Metformin
60 DLBS3233
Metformin + DLBS3233
40

20

0
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
 Effects of DLBS32 +/- Glimepiride on
Fasting Glucose Levels

160

150

140

Insulin Resistant
Fasting BG 130
Glimepiride
(mg/dl) 120
DLBS3233
Glimepiride + DLBS3233

110

100
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
 Effects of DLBS32 +/- Glimepiride on Fasting Total
Cholesterol and Trigliceride Levels
220

200

Total 180
Insulin Resistant
Cholesterol 160
Glimepiride
DLBS3233
(mg/dl) Glimepiride + DLBS3233
140

120
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment

160

140
Triglyceride 120

(mg/dl) 100
Insulin Resistant
80
Glimepiride
60 DLBS3233
Glimepiride + DLBS3233
40

20

0
7 days high-glucose diet 7 days treatment
Before treatment 14 days high-glucose diet 14 days treatment
 Prevention of Diabetes using DLBS3233 (Inlacin)

180

160
Control
DLBS3233 2.25 mg/kg
140 BW
Fasting BG
DLBS3233 4.5 mg/kg
(mg/dl) BW
120 DLBS3233 9 mg/kg BW
DLBS3233 18 mg/kg BW

100
7 days treatment 7 days on high glucose diet
before treatment 14 days treatment 14 days on high glucose diet
Prevention of Diabetes using DLBS3233
(Inlacin)
220

200

Control
180
DLBS3233 2.25
mg/kg BW
Total 160 DLBS3233 4.5 mg/kg
BW
Cholesterol 140 DLBS3233 9 mg/kg
BW
(mg/dl) DLBS3233 18 mg/kg
120
BW

100
7 days treatment 7 days on high glucose diet
before treatment 14 days treatment 14 days on high glucose diet

120

Triglyceride 100

(mg/dl) 80 Control
DLBS3233 2.25 mg/kg
BW
60
DLBS3233 4.5 mg/kg
BW
40
DLBS3233 9 mg/kg BW
DLBS3233 18 mg/kg
20 BW

0
7 days treatment 7 days on high glucose diet
bef ore treatment 14 days treatment 14 days on high glucose diet
Inlacin (DLBS3233) Safety Data

• At the end of study, no significant changes of laboratory safety

parameters (AP, ALT, Creatinine) were found in each group
• No clinically significant adverse events were observed during the study
period
DLBS-3233 and Its Low Risk of Hypoglycemia in
Normoglycemic Non-obese Healthy Subjects: A
Phase-I Study
Blood glucose profile after oral loading of
75-g glucose
 Inlacin (DLBS3233) Reduces HbA1c level
HbA1c HbA1c reduction from baseline (6 wk of
treatment)
11.00
0.20 0.08
10.50
10.27 0.00

HbA1c reduction (%)

HbA1c level (%)

10.00 -0.20 PLC D50

-0.40
9.58 PLC
9.50 9.50 -0.60
D50 D-HbA1c 6 wk
9.13 -0.80
9.00 -1.00
-1.20
8.50 -1.13
-1.40
8.00 -1.60
B-HbA1c E-HbA1c Group

Diabetes Complication Complication Risk Reduction

Diabetes-related death 21%
Myocardial Infarction 14%
Stroke 12%
Peripheral vascular disease 43%
Microvascular diseases 37%
Heart Failure 16%
 Inlacin (DLBS3233) decreases Plasma Fasting
Glucose level after 6 week therapy

FPG Percentage of FPG reduction from baseline (at

6 wk of treatment)
300.00

20.00
250.00 14.00
15.00
211.20 216.10 10.00
200.00 205.80
191.20
182.88 5.00
FPG level (mg/dL)

160.13 PLC 0.00

150.00

% FPG reduction
143.62 140.00 D50
-5.00 PLC D50 Percentage D-FPG 6
100.00 -10.00 wk
-15.00
50.00 -20.00
-25.00 -23.36
0.00
-30.00
baseline- 2wk FPG 4 wk FPG 6-wk FPG
FPG -35.00
Group Group
 Inlacin (DLBS3233) decreases Postprandial
Glucose level after 6 week therapy

PPPG PPPG reduction from baseline (at 6 wk of

400.00
treatment)

350.00
337.33 100.00
300.00
288.44 80.00
250.00 249.53
PPPG level (mg/dL)

237.14 60.00 48.89

PLC
200.00

eduction
D50 40.00 D-PPPG 6 wk

(mg/dL)
150.00
20.00
PGR
100.00
P
0.00
P

50.00
-20.00 PLC D50
-12.29
0.00
Baseline-PPBP 6-wk PPBG
Group
 Inlacin as mono and combination therapy

Mono therapy Combination Therapy

INLACIN 50 mg INLACIN + DPP4-INH
INLACIN 100 mg INLACIN + METFORMIN
INLACIN + SULFONILUREA
INLACIN + GLINID
INLACIN + INSULIN

It has been used by more than 12,105

patients as monotherapy or combination
therapy with the other OADs
 Clinical Experience with Inlacin in T2
DM – Real Cases

Duration of
Fasting 2 h PP HbA1c Treatment Treatment

Before After Before After Before After    

230 115 238 170 8.9 7.0 Monotherapy 1 month

250 120 380 180 10.0 7.8 Monotherapy 2 month

Combination
150  105  220 160 8.1  6.8  Therapy 1 month
 Conclusion
Molecular Roles of Inlacin (DLBS3233)
STIMULATION OF INSULIN – RECEPTOR
GLUCOSE TRANSPORT GLUT-4
CELL BINDING
MEMBRANE
EXERCISE 1

2 ATP
5’-AMP-ACTIVATED
KINASE 7 PROTEIN
KINASE B
(PKB) / Akt TYROSINE PHOSPHORYLATION
5a
4a 3
4
TRANSLOCATION PHOSPHOINOSITIDE-
TO CELL DEPENDENT p110 p85 IRS
Exercise-
Responsive MEMBRANE KINASES
GLUT-4 – 6 5b 4b PHOSPHOINOSITIDE-3
Containing ATYPICAL SH2
Vesicle PROTEIN KINASE (PI-3K)
KINASE C
Domains

Insulin-
Responsive
GLUT-4 –
Containing
6
Vesicle
 Conclusion


DLBS3233 has the activity to control the level of
blood sugar, insulin and other lipoproteins including
High Density Lipoprotein (HDL), Low Density
Lipoprotein (LDL), triglycerides, and total
cholesterol level.


DLBS3233 works well in reducing fasting and
postprandial glucose as well as HbA1C levels.
Thank You